FEVER IN THE RETURNED TRAVELER

0891-5520/98 $8.00

TRAVEL MEDICINE

+ .OO

FEVER IN THE RETURNED TRAVELER Alan J. Magill, MD

The image of an acutely ill, febrile patient who just returned from the depths of tropical Africa stirs the imagination and quickens the pulse of all clinicians. Could it be a rare "hot zone" virus causing hemorrhagic fever, a severe case of Plasmodium falciparum malaria, or some entirely new entity? In reality, it is just as likely to be a common infection acquired during travel, such as pneumonia or pyelonephritis or an illness unrelated to travel. Clinicians are faced with the daunting task of considering many exotic infectious agents, however, that North American physicians seldom encounter. There have been several reviews of this topic recently, especially the masterful assessment by Strickland,which contains many useful tables to assist in differential diagnosis.45, 133 In addition, others have provided clinically useful approaches to the evaluation of the febrile traveler to Southeast Asia and South loo and Latin America.&,82 Wilson's Guide to West Asia and the Middle World Infections is also an invaluable resource.153 APPROACH TO THE PATIENT

It is imperative that returning febrile travelers be thoroughly evaluated for all causes of their illness, both travel and nontravel related (Fig. 1). Many do not have an exotic tropical infection as the cause of their illness but, instead, have cosmopolitan infections or noninfectious causes of fever. It is a useful exercise to develop two differential diagnoses, one including the travel history and one ignoring the travel history. The objectives are to prevent serious morbidity or mortality from treatable diseases and to recognize potentially transmissible illnesses and prevent their spread to health care workers or case contacts. Therefore, initial diagnostic considerations should focus on acute, potentially The views of the author do not necessarily reflect the position of the Department of the Army or the Department of Defense

From the United States Naval Medical Research Institute Detachment (US NAMRID), Lima, Peru (on assignment from the Walter Reed Army Institute of Research, Washington, DC).

INFECTIOUS DISEASE CLINICS OF NORTH AMERICA VOLUME 12 * NUMBER 2 JUNE 1998

445

FEVER IN THE RETURNED TRAVELER

447

fatal diseases, such as malaria, and diseases that would require some form of isolation to prevent transmission to other health care workers, such as respiratory infections and the viral hemorrhagic fevers. Further complicating the evaluation of returned travelers is the fact that many of the tropical infectious diseases often have different clinical presentations in immunologically naive adults (travelers, expatriates, and soldiers) than in endemic populations. The classic descriptions of disease in adults from endemic areas can be misleading when applied to returning travelers. Disease in native children more closely resembles that seen in travelers, but there are still significant differences. Native children are a genetically distinct population, evolving over many generations of intimate contact with the local pathogens, so their immune responses are different. Also, illnesses are frequently more severe in adults than children (e.g., chickenpox, measles). In general, endemic populations have a higher “organism burden” (more parasites and bacteria) caused by prolonged contact and multiple exposures than do travelers. Travelers tend to have more symptomatic illness caused by fewer organisms. A lower organism burden can lead to decreased diagnostic sensitivity because for many diseases, especially those caused by parasites, diagnosis is often dependent on microscopic visualization of the pathogen.

EPIDEMIOLOGY The risk for acquiring a tropical infection is dramatically affected by the activities of the traveler. For example, adventure travelers have a much ”rougher” experience, traveling and sleeping in remote areas, with less control over their food sources and access to health care. Short-term tourists often stay in major hotels, frequent standard tourist destinations, and have fewer opportunities for exposure to vector- or food-borne pathogens. Long-term expatriates, such as Peace Corps volunteers, missionaries, and foreign service and military personnel, also have unique risk profiles. Unfortunately, there are few systematically collected data on the true incidence of fever, either during travel or within a defined period of time following travel. There are more review articles published on this topic than original

Figure 1. An algorithm for evaluation of fever in the returning traveler with emphasis on treatable, undifferentiated fever. *Hemorrhagicmanifestations include loss of blood by way of the gastrointestinal tract (hematemesis, melena), cutaneous signs (petechia, purpura), mucosal sources (epistaxis, gingival or conjunctival bleeding), or hematoria. tConsider flaviviruses (dengue hemorrhagic fever, yellow fever),arenaviruses (Lassa,South American hemorrhagic fevers), and bunyaviridae (Rift Valley fever, Crimean-Congo hemorrhagic fever, hemorrhagic fever with renal syndrome caused by hantavirus).*’ Although severe falciparum malaria has specific clinical, laboratory, and parasitologic criteria,Im in practice the patient at high risk can be quickly identified as an acutely ill patient (especially nonimmune) with signs or symptoms of end organ damage, such as impairment of consciousness, history of convulsions, prostration, jaundice, hyperpyrexia, respiratory distress, intractable vomiting, oliguria, or increased serum creatinine.* Empiric therapy with effective antimalarial regimens should be initiated when the patient is acutely ill and expert diagnostic microscopy is either not available or would result in a several-hour delay in therapy.

448

MAGILL

investigations. A recent report from the Zurich University Travel Clinic shows that 236 of 2109 (11.2Y0) evaluable patients reported a history of fever (although only about half had confirmed temperatures higher than 38°C) during or within 2 weeks of their These were German-speaking residents of Switzerland over the age of 13 traveling to developing countries and staying less than 13 weeks. Of those with fever, 161 (68.2%)reported their illness as incapacitating (defined in the study as inability to pursue plans because of a health impairment). The duration of incapacitation caused by fever was a mean of 3.3 days. Fever occurred with diarrhea in 92 of the travelers (40% of all fever). There were no deaths and only 9 hospitalizations in this group. These data reinforce the intuitive viewpoint that fever associated with significant illness is a relatively uncommon symptom in the millions who annually travel to overseas destinations. This is little comfort to the clinician, however, who is faced with evaluating an individual traveler. Two recent retrospective reviews summarized in Table 1 of an outpatient clinic and a hospital experience provide useful information. The final diagnosis for a consecutive series of 587 outpatients seen in Montreal between 1981 and 1987 showed that about one third of all fever cases (32%) were malaria.8oThis is by far the most common identified cause of fever. The next largest group (25%)was "unknown." These patients often present with an undifferentiated fever that resolved within 1 week or SQ. A specific etiologic diagnosis is never made despite efforts to do so and symptomatic or empiric therapy is often given. The remaining 43% of cases were widely distributed across the entire spectrum of infectious and noninfectious causes. A second series of 195 consecutive inpatients from the Hospital for Tropical Diseases in

Tabh 1. CAUSE OF FEVER AFTER TRAVEL TO THE TROPICS

Diagnosis Malaria Undiagnosed Other tropical Diarrheal illness Dengue Enteric fever Rickettsia Amebic liver abscess Cosmopolitan Hepatitis Respiratoryt Urinary tract Epstein-Barr virus Tuberculosis Pharyngitis Meningitis Acute HIV Miscettaneous

MacLean et at* (n = 587) 32

25 10.5 4.5

Doherty et al' (n=195) 42 25 15 6.5

2

6

2

2 0.5 0

1 1 6 11

4 2 1 1 1 0.3

6.3

3

2.5 2.5 0.5 2 2 1 1 5

'Values in table are percentages of total. tReflects upper respiratory tract infection, bronchitis, and pneumonia. Adapted from Doherly JF, Grant AD, Bryceson AD: Fever as the presenting complaint of travelers returning from the tropics. OJM 88277481, 1995; and MacLean J, blonde R, Ward B: Fever from the tropics. Travel Medicine Advisor 5:27.1-27.14, 1994; with permission.

FEVER IN THE RETURNED TRAVELER

449

London seen between November 1992 and April 1993 revealed similar Malaria was diagnosed in 42% of cases and undiagnosed fever was the next most common, causing 25% of cases. Interestingly, although these two series represent different population groups (inpatient versus outpatient) and two different locations (Montreal versus London), the etiologic agents of fever and the frequency of occurrence were similar. THE EVALUATION OF THE FEBRILE PATIENT An algorithm for the initial evaluation of febrile patients is presented in Figure 1. Although algorithms are useful reminders to the clinician who infrequently has to face a particular issue, they are never a replacement for a careful and complete evaluation of the individual patient using all available historical and epidemiologic clues. The initial evaluation should include questions directed toward the exact travel itinerary, with dates of arrival and departure, activities, and sleeping accommodations. In addition, specific questions to determine possible exposure risks to include fresh water contact, sexual contacts, animal exposures, unusual activities or hobbies, ill person contacts, and sources of food and water should follow. A complete medication history to include the type and compliance with malaria chemoprophylaxis is necessary and a determination of prior vaccination status to include both routine and travel vaccines is also necessary. A complete physical examination is required with emphasis on a thorough dermatologic examination, inspection of the eyes for evidence of scleral icterus, conjuctival suffusion, or conjunctival petechiae, and assessment for organomegaly or lymphadenopathy. Any abnormality should be pursued in a standard fashion consistent with laboratory and imaging facilities available. Routine laboratory evaluation usually includes a complete blood count, serum chemistry, liver profile, and a urinalysis. Thick and thin blood smears for malaria must always be performed if there is any possibility of that diagnosis. Additional special testing as directed by results of the history, physical examination, and preliminary laboratory tests will usually determine the etiologic agent or define the syndrome. Comprehensive reviews of the use of fever patterns in the differential diagnosis of febrile illness are available for the interested reader.36,79, But do fever patterns really help the clinician in today’s practice environment? The answer is a qualified “yes.” Careful questioning of patients about the pattern of fever and associated symptoms (sweats, rigors, chills, headache) in relation to the fever during the initial history can be quite useful. Prospectively, when temperature is accurately measured and recorded for 2 to 3 days, fever patterns can also be a useful diagnostic adjunct. Several real world problems, however, limit the usefulness of this time honored methodology. First of all, managed care organizations are reluctant to admit individuals for observation unless they are seriously ill. Even if the evaluation occurs as an inpatient, the author’s experience has been that it is difficult to get frequent, accurate, and properly recorded temperature results. Most hospitals perform vital sign checks once per shift (at varying times) and recording on bedside charts is sometimes incomplete or inaccurate. Trying to get more frequent temperature data points can be difficult with the personnel constraints in many hospitals. Consultation with the nursing staff to let them know the importance of frequent temperature recording for your patient may improve data collection. Patients may be the best source of this information (inpatient or outpatient) and can be instructed to take accurate oral temperatures and record the results. In addition, fever is often aggressively

450

MAGILL

treated with antipyretics, and concomitant use of other medications, such as corticosteroids, interferes with obtaining accurate measurements. Individual and age-related variations, changing hydration status, and environmental temperature changes can also make fever pattern interpretation difficult. DISEASE SPECIFIC COMMENTS

MaIaria By all historical and current measures, malaria is responsible for most of the preventable morbidity and mortality in returning travelers. Tragic stories of previously healthy travelers dying of this infection occur every year. Since 1990, about 1000 to 1200 cases per year of imported malaria have been reported to the US Centers for Disease Control and Prevention (CDC). Between 1991 and 1993, P. vivax was the cause in 43% to 52% of cases and P. falciparum was the cause in 33% to 39% of cases.21,'61Between 1980 and 1992, there were 45 fatal malaria infections among US civilians; 44 (98%) were caused by €? fakiparum. Thirty-six (82%) of these fatal cases were acquired in sub-Saharan Africa. Most cases were associated with the failure to use chemoprophylaxis, use of suboptimal chemoprophylactic regimens, delays in seeking medical attention, and delays in clinical and laboratory diagn0sis.4~Immigrants or expatriates visiting relatives in their home country, especially West Africa, are at higher risk. Although extremely uncommon, malaria can be acquired by travelers who transit through endemic areas ("airport" or "runway" malaria).63Rare, autochthonous transmission of malaria in nonendemic areas of the United States has also been reported.lM)Therefore, malaria should even be considered in those individuals without a typical exposure history. Once a febrile patient is under evaluation, the relative risk for malaria becomes moot. All febrile patients must be considered to have malaria until proven otherwise. One must then aggressively pursue the confirmation or exclusion of malaria by performing serial blood smears. There are no pathognomonic clinical signs or symptoms for malaria.@,137, A typical presentation in the nonimmune patient who has not taken any medication that could affect the malaria parasite consists of the abrupt onset of a paroxysm of rigors followed by fever and diaphoresis associated with profound malaise and severe headache. When accompanied by a low white blood cell count and platelet count, the diagnosis of malaria should be easy to consider. Many presentations are much less typical, however, and can easily mimic gastroenteritis or respiratory infections with focal findings. There is no clinical scenario that allows malaria to be 137 excluded from the differential diagnosis.I%* Once malaria is considered in the differential diagnosis, it can usually be easily confirmed or excluded by performing a blood smear. Lack of experience, however, with the optimal preparation, staining, and interpretation of malarial blood smears, especially thick blood films, in most laboratories of nonendemic countries continues to lead to errors in interpretation and delays in diagnosis.92 The microscopic diagnosis of malaria is an acquired skill that requires continuous practice to maintain proficiency. It is unrealistic to expect most laboratories to maintain this expertise on a 24 hour a day basis. Therefore, it is strongly suggested that clinics and health care professionals who see returning travelers either become proficient in the microscopic diagnosis of malaria themselves or identify a laboratory with qualified personnel before a crisis occurs. Trying to locate a reliable laboratory and identify qualified personnel to perform malaria

FEVER IN THE RETURNED TRAVELER

451

diagnosis when someone is critically ill can have tragic consequences. In some cases, laboratories may claim to have expertise but often this relies on one or two technicians who may have interpreted smears as part of remote training requirements. Demonstrated ability to prepare, stain, interpret, and quantify thick and thin smears is mandatory. Although much is made of the need to perform thick smears to reliably identify low parasitemias, do not forget the thin smear. A thin smear can be performed by almost every laboratory and quickly stained with standard hematology differential stains. When viewed under an oil immersion objective ( 1 0 0 ~magnification), parasitemias of greater than 1%(1 infected red blood cell (iRBC) per 100 RBCs) can easily be confirmed. Often parasitemias of 0.1% (1 iRBC per 1000 RBCs) or lower can be recognized. In addition, reliable species identification can be made on the thin smear allowing for prompt and optimal drug therapy. One must not forget that the clinician or laboratory technician who has never seen a malaria parasite outside of a textbook photo should not attempt to perform this skill without immediate verification by an expert. Artifacts on the smear can easily lead the inexperienced microscopist to make a false-positive diagnosis and poor staining combined with inexperience may lead one to make a false-negative diagnosis. Quantitation of the initial parasitemia is essential for choosing appropriate drug therapy, and subsequent quantifications are required for management and prognosis. Surprisingly, quantitation is often a difficult concept for laboratories to grasp. Although there are many different techniques that can be used, methods for routine clinical management can be quick and simple.%For example, one can count the number of asexual parasites per oil immersion field (OIF) in a thick smear. After counting the number of parasites per OIF in 10 to 20 OIFs and averaging, the result can be expressed as the number of parasites per OIF. If the presenting parasitemia is 40 parasites per OIF and the next day it is 15 parasites per OIF, then a decreasing parasitemia can be verified. Percentage parasitemia can be calculated by enumerating the number of iRBCs per 1000 RBCs of a thin smear. More accurate quantification can be made by multiplying the number of asexual parasites per 200 or 300 white blood cells (WBCs) on a thick smear by the quantitative WBC count (in WBCs per wL). This number expresses the absolute number of parasites per pL of blood but requires the WBC count be performed accurately and the smear be made from the same tube of blood used for the WBC count. Whatever method is chosen, consistency must be maintained during the management of an individual case. A new generation of rapid, nonmicroscopic diagnostic tests based on species-specific antigen detection will markedly improve the capability of inexperienced laboratories and physicians to accurately diagnose malaria. Although none of these tests are yet approved (as of mid-1998) by the FDA for use in the United States, test kits are available and being used overseas. Therefore, travelers may be exposed to these tests while overseas, and clinicians should be familiar with their use. Parasight F (Bedon Dickinson Microbiology Systems, Sparks, MD, USA) uses histidine-rich-protein-2 (HRP-2) specific monoclonal antibodies (Mabs) to detect antigenemia in whole blood from patients with asexual stage I? fulciparum parasites. Sensitivity of the current format is about 95% and specificity is more than 98% when compared with blood smears.* Cross-reactivity with other parasites has not been described. False positive reactions have been reported in patients with rheumatoid factor.= ICT Malaria P.f. (ICT Diagnostics, *References 20, 23, 39, 61, 67, 71, 106, 129, 141 and 145.

452

MAGILL

Sydney, Australia) also detects HRP-2 antigen in a rapid "dipstick assay. In a field trial from India in 98 febrile patients, ICT Malaria P.f. had a sensitivity, positive predictive value, negative predictive value, and specificity of loo%, 95.4%, loo%, and 98.9%, respectivelyn It is available commercially through distributors in Australia, Southeast Asia, India, and South Africa. Both Parasight F and ICT Malaria P.f. only detect l? falciparum infections at this time, although both companies are developing a P. vivax detection system. Optimal (Flow, Inc., Portland, Oregon) detects l? falciparum and l? vivax malaria using Mabs to parasite-specific lactate dehydrogenase (pLDH).=This format may be especially useful because pLDH seems to correlate with active parasitemia. Hopefully, in the near future a choice of rapid diagnostics for malaria will be available for the clinician to choose from. When can clinicians eliminate the diagnosis of malaria from the differential diagnosis of a febrile patient? Most symptomatic patients have a positive smear when first seen. In the series from London, all 82 inpatients with malaria had a positive smear when first performed on admission.40In a review of 482 cases of imported malaria, the diagnosis of malaria was confirmed on the first smear in 98%.137 On occasion, however, the diagnosis can be delayed up to several days because of low parasitemias associated with early clinical presentation in nonimmune patients or the presence of antimalarial drugs. In practice, clinicians should always consider the diagnosis of malaria until the illness completely resolves or another diagnosis is confirmed and the patient is responding to an appropriate intervention. The frequency of blood smear examinations is often recommended to be every 6 to 8 hours, while malaria is still in the differential; however, this may vary with severity of illness, and twice daily is often sufficient. l? vivax, l? ovule, and l? malariae are always in the peripheral blood (no sequestered forms) so there is no optimal timing of the blood smear in relation to fever. Infected RBCs containing mature l? fakiparum parasites are sequestered (adhere by way of specific receptor-ligand interactions to the endothelium of postcapillary venules of many tissues) and so may not be in peripheral blood at the time blood is sampled. P. fakiparum parasites remain in the peripheral circulation for at least 12 hours after a typical paroxysm. One must always remember that patients who have taken chemoprophylaxis during travel may have a different, less severe, clinical disease.75,150 These individuals may present with a less acute illness of more insidious onset and atypical symptoms, such as intermittent low-grade fever, lumbosacral muscle pain, fatigue, malaise, and nonspecific gastrointestinal symptoms. Afebrile cases have also been rep0rted.8~This illness of attenuated severity is associated with prolonged pre-patent periods as drugs taken for chemoprophylaxis, such as mefloquine (MQ) or chloroquine (CQ), have long half-lives (up to 30 Patients may present weeks or months after returning from endemic areas. Travelers may be taking drugs for other indications, which may be effective chemoprophylaxis agents, such as doxycycline, or less effective agents, such as chloramphenicol and clindamycin, and not volunteer a history of malaria chemoprophylaxis. Some medications can also interfere with the metabolism of commonly used antimalarial drugs. An example is the decrease in serum halflife of oral doxycycline when used with carbamazepine, a common antiseizure medication.gs Theoretically, these individuals could have intermittent "break through parasitemias responsible for mild symptoms. Another possibility is the improper use of antimalarial medications for the empiric therapy of febrile illness. Individuals who clinically improved and then relapsed after receiving doxycycline as empiric therapy for their misdiagnosed malaria have been reported.'=

FEVER IN THE RETURNED TRAVELER

453

Finally, clinicians should have a low threshold for empiric therapy if the diagnosis of malaria, especially P. falcipururn malaria, is possible and reliable diagnostic services are not available. Clinicians should not delay therapy while trying to locate an appropriate facility to perform specific testing, especially when patients have signs of severe malaria, such as respiratory distress, disorientation, or confusion. Early therapy is often oral, relatively easy to administer and monitor, and can prevent a tragedy. Delay can result in parenteral therapy, difficult and expensive management of an acutely ill patient with multiorgan failure, and a marked increase in mortality. Mefloquine (Larium, Hoffman La Roche) is an effective oral therapy for all forms of malaria (with the exception of multiple drug-resistant falciparum malaria acquired along the Thailand-Myanmar and Thailand-Cambodia borders). The manufacturer’s recommended dosage is 1250 mg (5 tablets) given as a single dose. This single dose therapy is poorly tolerated by patients, and split dosing is preferred. Giving 750 mg followed by 500 mg 24 hours later is just as effective, pharmacokinetically equivalent and much better t0lerated.9~For those who become symptomatic while on MQ prophylaxis, oral or intravenous quinine (intravenous quinidine gluconate in the United States) as clinically indicated is recommended to avoid the possibility of MQ toxicity. Both prophylaxis and treatment failures with MQ have been reported from many areas around the world outside so use of mefloquine therapeutically to treat a patient who of Southeast may have failed mefloquine prophylaxis is not recommended. The first reliable reports of chloroquine resistant P. vivux (CRPV) appeared in 1989. Rieckman et a1 reported two nonimmune Australian soldiers who had breakthroughs while on CQ prophylaxis.i10Several reports have followed.*Most cases were reported from New Guinea, Indonesia, and the surrounding islands. Reports from Myanmar and India suggest that CRPV is also present on the Southeast Asian mainland and Indian s u b c ~ n t i n e n tThere . ~ ~ ~are ~ ~two confirmed cases of CRPV from Guyana (South America) in returning travelers.’” One should consider the possibility of CRPV from areas in which it is currently not reported because its presence in other areas is likely. Patients with documented I? vivax infection should receive the recommended dose of CQ for nonimmunes (25 mg of base per kg) over 3 days combined with an effective dose of primaquine (PQ) to eradicate the hypnozoite form in the liver. This regimen should prevent a recrudescent I? vivux infection. To detect and document CRPV, drug therapy should be directly observed to ensure compliance. Blood smears should be obtained at 3, 7, and 28 days following therapy to document clearance of parasites and possible recurrence. If patients become parasitemic within the 28-day period, clinicians can presume CRPV and the patient should be re-treated with quinine plus doxycycline or MQ. Although desirable, this “academic” approach may be logistically or financially difficult for some. The current recommended dose of PQ is 15 mg base per day for 14 days (210 mg PQ base total dose). There are numerous reports of clinical failures with this regimen, although noncompliance cannot be excluded as a cause for at least some failures. Many experts now recommend 30 mg base per day for 14 days (420 mg PQ base total dose) for all confirmed P. vivux infections. This recommendation is consistent with estimates that a minimum of 6 mg per kg of PQ is required to eradicate the hypnozoite stage.32For a ”typical” 70 kg person, the 30 mg per day for 14 day regimen is equivalent to 6 mg per kg. *References 19, 33,34,46, 54, 72’96, 113, 120, 121, 124, and 151.

454

MAGILL

Quinidine gluconate (the dextrorotary diastereoisomer of quinine) is the only parenteral therapy for the treatment of complicated malaria commercially available in the United state^.^,^,^^ Quinidine was widely available in the United States because of its use as a treatment for persons with cardiac dysrhythmias. It is no longer a preferred drug for this indication, however, and it is no longer available in some hospital formularies.", This has contributed to fatal outcomes.62Because there is no parenteral alternative, ready availability of parenteral quinidine is mandatory for all those who may be asked to care for such individuals. Proactive efforts to identdy local sources are warranted to avert a crisis situation. In addition, hospital formularies should be reviewed, and if the drug has been removed, then appropriate consultation and recommendations from the infectious disease consultant can restore this important drug to the formulary.

Schistosomiasis

Although there have been many reports over the years of schistosomiasis in travelers, it is often not considered to be an important cause of fever or illness. The nonspecific clinical presentation of acute schistosomiasis, however, and the extremely high attack rate reported in outbreak investigations make it likely that this infection is underreported. The potential of serious sequelae of untreated infections, increasing availability of sensitive and specific serologic tests, and the success of praziquantel in the treatment of this infection argue for an increased awareness of schistosomias in the returhing traveler. Schistosomiasisis a common parasitic infection caused by trematodes (blood flukes) endemic to large areas of Africa, Asia, South America, and the Caribbean.78Three species commonly cause human disease: s. rnansoni, s. haernatobiurn, and S. japonicurn. After fork tailed cercariae are released from infected snails, they penetrate the skin of people in contact with contaminated water. Entry of the cercariae through the skin provokes an immediate tingling and itching at the site followed within an hour by a short lived macular rash. Twelve to 24 hours later, an intensely pruritic, urticaria1 or papulovesicular eruption may occur lasting for days. When a history of cercarial dermatitis can be elicited in association with a freshwater exposure, it is a useful clue. The presence and severity of dermatitis depend on prior sensitization, however, and completely naive travelers may not experience this symptom. Many North Americans are already sensitized to schistosomes from exposure to nonhuman (avian or mammalian) cercariae encountered in many freshwater and coastal areas of North America where it is often referred to as "swimmer's i t c h or "clamdigger's itch." The cercariae migrate through the lungs and liver before passing to their final habitat in the portal veins (S. rnansoni and S. japonicurn) or the urinary bladder plexus (S. haernatobiurn) in which they mature into adults, mate, and begin egg deposition. The early migratory phase through the lungs can cause a severe illness.48About 4 to 8 weeks later, egg deposition by maturing schistosomes leads to the syndrome of acute schistosomiasis (also known as Katayama fever), which is thought to be an immune complex phenomenon. Most individuals recover without specific therapy but it can be fatal. Long-term complications that arise from chronic infection with a high adult worm and egg burden are liver fibrosis and portal hypertension in the intestinal form and obstructive uropathy, hematuria and, possibly, bladder cancer in the urinary form. This pathology is not seen in travelers or most expatriates because of limited expo-

FEVER IN THE RETURNED TRAVELER

455

sures leading to a light worm burden and minimal egg deposition. The adult worms can live for years, however, periodically producing viable eggs.% Acute schistosomiasis in returning travelers can be a severe, generalized, febrile, illness, although less severe illness is more common. Between August 1994 and December 1995, 488 cases of egg or antibody-positive schistosomiasis in returning travelers were reported from the Hospital for Tropical Diseases in London along with 16 cases of acute schistosomiasis.41A previously reported series of 344 confirmed cases from the same hospital with only 2 cases of acute schistosomiasis confirms that the acute syndrome is uncommon compared to the total number of infections.%Symptoms were nonspecific with fever, myalgias and profound lethargy being the most Other symptoms included cough, headache, and anorexia. A normal physical examination was recorded in 9 individuals, urticaria1 rash in 2, and tender hepatosplenomegaly in 4 cases. Only 2 recalled having "swimmers itch." Laboratory examination was remarkable for eosinophilia in 14 of 16. Only 1 patient was parasitologically confirmed before treatment. All patients subsequently developed antibodies to soluble egg antigen with time to seroconversion (mean of 1.6 months, range 0 to 6 months). There have been several outbreaks of Katayama fever in groups of travelers or expatriates.* These outbreaks were characterized by a high attack rate of 79% (73/92), were associated with swimming or rafting in nonimmune travelers or expatriate residents, and almost all were associated with S. mansoni. A history of cercarial dermatitis was useful when present, but its absence did not exclude the diagnosis. Cases were characterized by very low egg counts, making parasitological confirmation difficult. Eosinophilia higher than 1000/mm3 was seen in all but four of the cases. In those in which the eosinophil count was not sigruficantly elevated, the patients were asymptomatic or minimally symptomatic. It seems that severity roughly parallels the eosinophil count. Reported cases probably underestimate the number of acute infections in returning travelers because identification of an index case often leads to others in the group who would otherwise be symptomatic with an "undiagnosed illness.'' Three of four members of an Italian family visiting Lake Malawi became infected with S. haematobiurn following a brief swimming exposure.10gThe wife, who did not swim, was not infected. Two of these three became symptomatic 2 months after returning to Italy with perineal discomfort, urinary frequency, and hematuria. One remained asymptomatic. All three were egg positive on examination of concentrated urine. Importantly, the index case in this family was investigated for over a year before the diagnosis of urinary schistosomiasis was considered. Although not usually presenting with fever, it is important to consider neuroschistosomiasis caused by ectopic egg deposition as the other important clinical syndrome seen in travelers with schistosomal infection. Anomalous migration of adult worms into the central nervous system with local egg deposition or hematogenous dissemination of eggs are both thought to occur.z, 59, 74, 126 Cerebral schistosomiasis, thought to be more common with S. japonicum and S. haematobiurn, may present as a space occupying lesion with increased intracranial pressure, hemianopsia, nystagmus, vertigo, or encephalopathy. Transverse myelitis is the most commonly recognized central nervous system complication of S. mansoni infections." Neuroschistosomiasis has been reported in travelers and expatriates.6,24,26.105.127

The diagnosis of schistosomiasis should be suspected in any returning traveler with a history of freshwater exposure in an endemic area with unex*References 1, 30, 31,64, 104, 118,135, 146 and 162.

456

MAGILL

plained systemic, intestinal, genitourinary, or neurologic symptoms. An aggressive search for schistosome eggs should begin with examination of the urine sediment or stool. If no eggs are seen, then concentration methods should be used to improve sensitivity. Rectal or bladder biopsies can then be used if no eggs are found in urine or stool samples. Failure to visualize eggs does not exclude the diagnosis. In the United States, serologic tests can be obtained from the CDC by calling (770) 480-7775.The CDC offers an ELISA screening test (sensitivity and specificity of 99%) and a confirmatory immunoblot (specificity 100%) that can determine the infecting species based on the use of an adult worm microsomal antigen.140 A negative CDC serologic test effectively excludes (except for very early infections) the diagnosis of schistosomiasis. Commercial assays are also At this time, the benefit of screening asymptomatic travelers with a history of freshwater exposure for schistosomiasis with a serologic test is unclear. Praziquantel is considered the drug of choice for the treatment of all forms of schistosomiasis.128 The recommended dose is 20 mg per kg every four hours for a total of three doses. Although there is some controversy over the efficacy of praziquantel in acute schistosomiasis,'58current recommendations are to promptly treat all patients. The use of corticosteroids is recommended for severe systemic disease and suspected neuroschistosomiasis to minimize inflammat i ~ nIf. a~ patient ~ has a compatible exposure history with a potentially devastating clinical syndrome, such as progressive neurologic impairment, empiric therapy is indicated while awaiting the results of specific serology. Treatment of the asymptomatic traveler with a positive serologic test is probably indicated, although still controversial. For travelers and clinicians, the knowledge that even brief freshwater exposures can lead to infection should lead to warnings to avoid exposure in fresh water regardless of how hot the day is or how inviting the water. For adventure travelers who participate in rafting or white water expeditions, there are currently no recommendations on ways to prevent possible exposures. Enteric Fevers

Enteric fever refers to a clinical syndrome characterized by a wide variety of symptoms to include fever, headache, malaise, and frequent gastrointestinal symptoms (diarrhea, constipation, vomiting, and anorexia) caused by infection with Salmonella typhi (typhoid fever) or Salmonella paratyphi (paratyphoid fever). Incubation period is 1 to 3 weeks following ingestion of bacteria. Retrospective reviews from major urban centers in the United States and elsewhere show that most cases seen in the United States are imported and children and adolescents are at highest risk.88,93 Enteric fever is still common in many developing countries with a markedly higher risk of acquiring infection in the Indian subcontinent.88,'32 As there are no distinctive clinical features, the diagnosis should be considered in all febrile patients, even those without gastrointestinal symptoms. Laboratory findings are nonspecific, with anemia, leukopenia, and elevated transaminases commonly seen. Appropriate cultures should be performed to confirm the diagnosis. Peripheral blood, bone marrow, buffy coat, urine, stool, and gastric or duodenal aspirates have all been successfully cultured with varying sensitivity. In practice, blood cultures performed before the use of antibiotics are usually positive after a few days of illness. Prior or concurrent antibiotic use decreases sensitivity. Multidrug-resistant (MDR) strains of S. &phi (resistant to chloramphenicol,

FEVER IN THE RETURNED TRAVELER

457

ampicillin, and trimethoprim) are now common from many different geographic areas.117A ciprofloxacin resistant isolate was first reported from the United Kingdom in 1992 from a 1-year-old who acquired the infection in India and did not respond to therapy.115,142 Subsequently, chromosomally mediated resistance associated with Vi phage type E l has been identified in other MDR isolates from patients returning from the Indian subcontinent.116Despite the documentation of ciprofloxacin resistance in a few cases, ciprofloxacin remains the current recommended therapy, at least until in vitro antibiotic sensitivity profiles are available. Currently approved Salmonella typhi vaccines have an efficacy of 70% to 90% and most authorities recommend typhoid vaccination for travelers from developed countries to developing countries, particularly those planning to visit the Indian subcontinent. Vaccination clearly does not prevent all cases of enteric fever, however, and there is less of a beneficial effect against the paratyphi strains.lz3Therefore, a history of typhoid vaccination does not exclude the diagnosis of enteric fever. Rickettsial Infections

Rickettsia1 diseases are widely distributed throughout the world. They are commonly divided into the spotted fevers, typhus fever, and Q fever. With the exception of Q fever, they are all vector-borne (usually tick) zoonoses sharing many clinical features. The abrupt onset of fever with prominent headache is common. Rickettsial infections are probably more common in travelers than currently appreciated. Between 1988 and 1993, 60 cases of rickettsia1 infection (estimated as the third most common cause of imported febrile disease) were reported to the Swiss Federal Office of Public Health in returning travelers.lo8Two thirds were caused by Rickettsia conori, the causative agent of African tick typhus (also known as Boutonneuse fever, Mediterranean spotted fever, Kenya tick typhus, and others). R. conori is transmitted by a variety of hard ticks with an incubation period of 5 to 7 days. It has a widespread distribution throughout Africa, the Middle East, India, and the Mediterranean basin. Incidence in endemic areas seems to be increasing, and cases are being reported in areas in which it was previously unknown or unusual. Illness frequently begins with abrupt onset of fever, headache, myalgia, maculopapular rashes, and malaise. Commonly there is a primary lesion at the bite site called the ”tiiche noire” or black spot, described as a 2 to 10 mm eschar with surrounding erythema. The tiiche noire is present for 1 to 2 weeks and regional adenopathy is frequent. Marschang et a1 reported 22 cases of rickettsiosis imported to Germany (13 men, 9 women, average age 42 years) in a 5-year period.% The cases were analyzed retrospectively regarding the travel histories, symptoms, and clinical findings, laboratory features, and course of the disease. The two primary rickettsial diseases were Boutonneuse fever (18 patients) and scrub typhus (3 patients). One patient had murine typhus. The main symptom was fever in 91%, followed myalgia (40%), arthralgia (50%), and diarrhea (36%). The by headache (&I%), most frequent clinical finding was lymphadenopathy in 65%. Eschar was detectable in 55% of patients with R. conori infection and in one patient with R. tsutsugamushi infection. All patients with R. tsutsugamushi infection and 33% of the patients with R. conori infection had a macular exanthem. One patient with scrub typhus had pleural and pericardial effusions. Seventy-three percent had an increased erythrocyte sedimentation rate (ESR). Three patients had leukocyto-

458

MAGKL

sis, three increased transaminases, and two normochromic anemia. The incubation period for R. conori infection was 5 to 28 days (average 14 days) and 7 to 21 days (average 16 days) for R. tsutsugarnushi infection. Twenty-one patients were treated with tetracycline or doxycycline, one with erythromycin. All patients were cured, although one patient relapsed. In another report, 9 of 10 patients reported tick contact during hunts in high grass.'07 The huntsmen acquired their disease in South Africa (6), Zimbabwe (l),and Mozambique (I). The tenth reported contact with a dog near a hotel in Kinshasa, Zaire. All presented with typical signs and symptoms and a maculopapular rash, although only 8 of the 10 had eschars. In January 1992, 169 US soldiers participated in a 10-day training exercise in Botswana. Within 2 days of their return to Italy, about 30% sought medical attention for fever, sweats, headache, right upper quadrant (RUQ) tenderness, adenopathy, and atypical insect bites. An investigation using questionnaires, directed physical examinations, and comparison of acute and convalescent titers revealed 39 cases of African tick typhus for an attack rate of 23%. Twenty-four cases showed seroconversion (greater than or equal to a fourfold rise in R. conorii IgG by IFA and a convalescent titer greater than 1:64), whereas the remaining 15 had the tsche noire plus adenopathy; 40% had more than one tsche noire.I3' All individuals were treated with doxycycline and recovered without complications. This experience shows that R. conqrii is capable of causing epidemic outbreaks in the right ecologic setting. Additional case reports of other rickettsia1infections leading to severe illness and fatalities in returning travelers include murine typhus from India5 and scrub typhus from Vietnam and Thailand.139, 149 A presumptive clinical diagnosis is usually made by the combination of compatible exposure history and clinical findings (presence of eschar) and then confirmed by serology. Empiric treatment should be initiated based on clinical suspicion while waiting for serologic confirmation because these test results are often not completed in a clinically meaningful period. Fatalities caused by R. conori, even in untreated cases, are uncommon YO to 2%), but entirely preventable. A rapid clinical response often follows oral doxycycline, 100 mg twice daily for 7 days.

Leptospirosis Leptospirosis is a common, cosmopolitan zoonosis infecting wild and domestic animals that excrete the causative spirochete in their urine. Humans become infected when leptospires enter through abraded skin, mucous membranes, or conjunctivae following contact with urine contaminated water or soil." Epidemiologically, infected individuals usually have a history of contact with dogs; swimming, rafting, or wading in contaminated fresh surface water; or farming and gardening in soil contaminated with leptospires. A recent epidemic of leptospirosis with some cases of severe pulmonary hemorrhage was reported from Nicaragua.'= Human leptospirosis is caused by numerous serovars. The classic presentation of leptospirosis is that of a biphasic illness. The initial septicemic phase lasts 4 to 7 days and is characterized most commonly as an influenza-like illness. Common symptoms include fever, chills, headache, myalgia, and nausea. Conjunctivitis with conjunctival suffusion and muscle tenderness are useful physical findings when present. During the secondary immune phase, leptospires disappear from the blood and cerebrospinal fluid, but circulating antibod-

FEVER IN THE RETURNED TRAVELER

459

ies cause immune-mediated meningitis, uveitis, rash, and, very rarely, circulatory collapse. Severe illness with jaundice, renal failure, pulmonary failure, hemorPulmonary involvement occurs in 20% rhage, and death is seen in 5% to 10Y0.~ to 70% of patients to include atypical pneumonia, acute respiratory distress syndrome (ARE), and hem~rrhage?~, 99 Severe and fatal hemorrhagic fever syndromes, jaundice with liver failure (Weil's disease), and neurologic syndromes have all been described in returning travelers.95,143 Recently, an outbreak of leptospirosis was reported among white water rafters after a trip in Costa Rica.15Nine of 26 rafters (35%) had an illness defined as fever associated with rigors, headaches, and myalgias. The median incubation period was 12 days. Illness was strongly correlated with ingestion of river water and submersion underwater after falling into the river while rafting through rapids. Symptoms were self-limited in three, six were placed on antibiotic therapy, and two were hospitalized. In the Netherlands between 1987 and 1991, 14% of the total number of cases of leptospirosis reported were seen in returning tra~e1ers.l~~ All but 1 of the 32 reported cases in travelers had contact with natural bodies of water. Twentyfour patients acquired their infections while white water rafting in Thailand. Although leptospires can be relatively easily isolated from blood or cerebrospinal fluid during the early phase of illness using special media, culture is not commonly requested or performed. Diagnosis is usually established retrospectively by serologic tests. The most reliable serologic test for leptospirosis is the microscopic agglutination test (MAT). This assay is available at the CDC through referral by state health departments. ELISA tests for both IgM and IgG antibodies are available, but sensitivity and specificity vary widely. New rapid test formats promise results in a clinically meaningful time frame?* Oral doxycycline given in the first 3 days of illness decreases severity and duration of symptoms and may prevent complications and mortalityg0In severe cases, intravenous penicillin is effective even when treatment is delayed.I4* Jarisch-Herxheimerreactions have been reported following thera~y.4~.Individuals with pulmonary hemorrhage and acute renal failure require intensive care but recover completely if supported adequately. Chemoprophylaxis with doxycycline is effective and could be considered for high-risk individual^.'^^ Empiric therapy with oral doxycycline or intravenous penicillin (or ampicillin) should be considered if the diagnosis of leptospirosis is epidemiologically and clinically possible. Dengue fever

Dengue is a mosquito transmitted viral disease caused by any of the four virus serotypes (DEN-1, DEN-2, DEN-3, and DEN-4). Infection with dengue virus usually leads to classic dengue fever (DF) characterized by the acute onset of fever, frontal headache, retro-ocular pain, myalgias, arthralgias, and rash. More severe manifestations include dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS).DHF is defined as DF with hemorrhagic manifestations, thrombocytopenia (less than or equal to 100,000/mm3), and objective evidence of increased capillary permeability (hemoconcentration, pleural effusion, or hypoalbuminemia). DSS occurs when hypotension or narrow pulse pressure (less than or equal to 20 mm Hg) accompanies the signs of DHF.I4 The incidence and geographic range of dengue has increased from the mid-1970s and is now resurgent worldwide?l DF is the most common arboviral etiology of fever in returned travelers.", ffi, 89, lI9, 122, 155

460

MAGILL

Between 1986 and 1995, the CDC processed serum samples from 1377 suspected cases for the diagnosis of dengue?, Dengue was confirmed serologically or virologically in 289 (21%)of the cases. 181 (63%) of the cases were acquired from Latin America or the Carribean basin, 78 (27%) from Asia or Oceania, and 12 (4%) from Africa. Some individuals had traveled to more than one continent. All four dengue virus serotypes were isolated from travelers. In the US Virgin Islands and Puerto Rico, three serotypes (DEN-1, DEN-2, and DEN-4) circulated during 1986 through 1992. In Puerto Rico, disease transmission was characterized by a cyclical pattern, with peaks in incidence occurring during months with higher temperatures and humidity (usually from September through November). The CDC data are likely an underestimate as many cases of imported dengue are probably not confirmed or not reported. Although the number of laboratory diagnosed dengue infections among travelers was small, severe and fatal disease was documented. The incubation period for dengue was 3 to 10 days. Most travelers presented with signs and symptoms of DF with fever reported in 95% to 1007'0, headaches in 40% to 70%, myalgias in 48% to 55%, and rash in 48% to 54%.9,l2 The typical rash associated with dengue is a a bright macular or maculopapular truncal erythroderma that blanches dramatically under light pressure. Retro-orbital pain on lateral movement of the eyes, although not specific for dengue, is not seen in other diagnoses, such as malaria and enteric fever. Frontal headache, retroocular pain (exacerbated with movement of the eyes), and rash strongly suggest dengue. Hospitalization was required in 1%to 2%of cakes, and there was at least one fatality. Occasional cases of DHF and DSS were reported but uncommon. Leukopenia, thrombocytopenia, and elevated liver enzymes are common but not specific. The diagnosis is made clinically and confirmed in the laboratory by virus isolation, demonstration of dengue virus antigen, demonstration of an elevated IgM antibody titer to one or more dengue antigens, or a fourfold increase or higher in IgG titers in paired acute and convalescent serum samples. Specimens should be sent through state health departments to the CDC. Although there is no specific therapy for DF, patients should be monitored for signs of DHF and DSS. Acetaminophen is recommended for the management of fever and other symptoms to avoid the anticoagulant properties of aspirin and nonsteroidal antiinflammatory medications. UNCOMMON TROPICAL CAUSES OF FEVER IN THE RETURNED TRAVEL Parasitic

Visceral leishmaniasis is occasionally reported in returning travelers, especially Europeans from nonendemic countries such as Scandinavia and the United Kingdom who vacation in endemic areas of the Mediterranean Basin. Patients with HIV infection may be at particular risk. Most patients present with some combination of the typical signs and symptoms of visceral leishmaniasis to include fever, weight loss, hepatosplenomegaly, pancytopenia, and hypergammaglobulinemia weeks to months after exposure.16, Io2 Presentations can be mistaken for hematologic malignancies.@ African trypanosomiasis is rare in travelers but has been occasionally seen in tourists visiting the East African game parks and hunters. Fifteen American travelers were treated for East African trypanosomiasis in the United States

FEVER IN THE RETURNED TRAVELER

461

between 1967 and 1987; no cases were acquired in West Africa.z9Cases were from 8 countries in East Africa, 11 of 15 (73%) travelers were participating in organized safaris, and the only significant epidemiologic risk factor was exposure to tsetse flies. Cases occurred year round (8 of 12 months), and duration of exposure was not significant as all travel was limited to a few days to weeks. The incubation period was 6 to 28 days with 12 of 15 (80%) noting symptom onset within 14 days of the tsetse bite. Fever was universal, trypanosomal chancres were present in 10 of 15 (67'/0), and a trypanosomal rash was described in 7 of 15 (47%). Diagnosis was confirmed by demonstration of parasites in Wright stained peripheral blood smears or cerebral spinal fluid. Only 2 of 15 (13%) had documented CNS involvement, both associated with a delay in diagnosis (10 and 15 days). Many of these patients were described as very ill with thrombocytopenia, anemia, leukopenia, disseminated intravascular coagulation (DIC), renal dysfunction, hyponatremia, and cardiac decompensation with hypoxia. Hospitalization, including ICU care, was required for all cases (6 to 32 days). All patients were treated with suramin and the two with CNS involvement received melarsoprol. All patients recovered, although one had a severe reaction consistent with reactive encephalopathy. Panosian et a1 conclude that early recognition and prompt therapy before CNS invasion decreases morbidity. Since 1987, one additional case has been reported.'O' Amebic liver abscess is occasionally a cause of fever in the returned traveler. The development of abdominal pain localizing to the right upper quadrant, hepatomegaly and an elevated peripheral white blood cell count suggest the diagnosis. Imaging studies of the liver, usually showing a solitary abscess in the right lobe, and elevated antibody titers in the appropriate clinical setting virtually confirm the diagnosis. Therapy with metronidazole is usually effective.73 Bacterial

Starting in 1990 an epidemic of diphtheria emerged in the newly independent states of the Soviet Union affecting all 15 countries by 1994.8 Since the epidemic began there have been about 125,000 cases and over 4000 deaths.13 Two cases of diphtheria presenting as membranous pharyngitis have been documented in returning US citizens7 Cutaneous diphtheria presenting as cellulitis with a central necrotic area has also been reported from Bali.17Diptheria immunization should be regularly updated for all travelers. Clinical and laboratory recognition of this infection is essential. Diptheria antitoxin, available through the CDC, is effective and life-saving therapy. Invasive gastrointestinal pathogens such as Shigella, Salmonella, Campylobacter, and enterotoxigenic Escherichia coli (ETEC) are common causes of fever in the returned traveler but these pathogens do not present a diagnostic dilemma because they are associated with abdominal pain and diarrhea. Persons with Shigella and ETEC often have a systemic oniet to their illness with fever and chills, but abdominal symptoms and signs appear within hours. Brucellosis is uncommon but should be considered in anyone with fever and prominent musculoskeletal complaints. A history of ingestion of unpasteurized dairy products, especially goat cheese, is an important clue.I8Pseudomonas pseudomallei, the causative agent of melioidosis, is a common cause of community acquired septicemia in Southeast Asia and parts of Northern Australia. A fatal case in a tourist who acquired melioidosis in Thailand despite intensive intravenous therapy with antibiotics to which the organism was sensitive was de-

462

MAGlLL

Viral

Imported cases of viral hemorrhagic fever are rare.58,70,Iz5 International travel and immigration, however, make importation possible, and physicians should consider an exotic viral hemorrhagic fever in any traveler or recent immigrant who develops a febrile illness with hemorrhagic manifestations within 3 weeks of returning from an endemic area. One must also consider an occupational exposure in laboratory personnel, workers exposed to animals from endemic areas, and health care workers at risk for nosocomial transmission who present with fever and bleeding manifestations. Management of infected persons includes intensive supportive care during the acute infection and appropriate use of ribavirimz,lo Fortunately, protective measures are already in place in US hospitals and laboratories because of universal precautions policies implemented to prevent the transmission of H N and hepatitis B. All suspected cases of viral hemorrhagic fever should be reported to the Special Pathogens Branch, Centers for Disease Control and Prevention, Atlanta, Georgia. Assistance in the management and diagnosis of these cases can be obtained emergently by calling (404) 639-2888 after hours and on weekends; and (404)639-1510 during business hours. Sylvatic yellow fever is resurgent in sub-Saharan Africa and the Amazon basin of South America.11zThe yellow fever vaccine is extremely effective and a history of vaccination virtually excludes the possibility of yellow fever in the differential diagnosis of a febrile patient. Failure to receive the yellow fever vaccine before visiting the Amazon basin has led to confirmed fatalities in travelers." 90a Viral hepatitis, especially hepatitis A, has historically been a common cause of fever in returning traveler~.s.5~*'~~ Increasing use of the hepatitis A vaccine will probably markedly decrease the incidence of this infection in those travelers who receive the vaccine. Hepatitis B continues to be a risk for those individuals not vaccinated and with sexual or occupational exposures while traveling. Other enteric forms of viral hepatitis, especially hepatitis E (HEV), will be increasingly recognized in travelers5, as awareness of the disease and serologic tests become a~ailable.2~ HEV is responsible for acute sporadic hepatitis and epidemics. Transmission is by the fecal-oral route and the incubation period averages 45 days (range of 2 to 9 weeks). The typical clinical presentation of jaundice with marked elevations in transaminase levels makes the clinical consideration and serologic confirmation of these disorders relatively straightforword. SUMMARY

The most important cause of fever in the returned traveler is malaria. AU febrile patients in which malaria is epidemiologically possible require urgent evaluation for I? falcipurum malaria, which can be rapidly fatal in the nonimmune patient. Early diagnosis and therapy can prevent severe morbidity and mortality. Other less common causes of undifferentiated fever include acute schistosomiasis, the enteric fevers, rickettsial diseases, leptospirosis, and dengue fever. Early empiric therapy for suspected leptospirosis and the rickettsial infections is encouraged to decrease morbidity and mortality. About a quarter of febrile patients do not have an etiologic agent determined for their illness but recover without sequelae. Patients with fever and hemorrhagic manifestations within 3 weeks of their return need to be isolated for the remote possibility of a highly transmissible agent. Although the febrile traveler is always a challenge, the real world differential diagnosis is limited and a systematic approach via the history,

FEVER IN THE RETURNED TRAVELER

463

physical examination, and selected laboratory tests is usually sufficient t o confirm the diagnosis or eliminate potentially serious infections. ACKNOWLEDGMENTS I would like to thank JG Babcock, MD, for her thoughtful review of the manuscript and A1 Reynolds, reference librarian for the Walter Reed Army Institute of Research, for his professional support.

References 1. Cercarial dermatitis among bathers in California; Katayama syndrome among travelers to Ethiopia. MMWR Morb Mortal Wkly Rep 31:435-438, 1982 2. Management of patients with suspected viral hemorrhagic fever. MMWR Morb Mortal Wkly Rep 371-15,1988 3. Treatment of severe Plasmodium falciparum malaria with quinidine gluconate: Discontinuation of parenteral quinine from CDC drug service. MMWR Morb Mortal Wkly Rep 40240,1991 4. Treatment with quinidine gluconate of persons with severe Plasmodium falciparum infection: discontinuation of parenteral quinine from CDC Drug Service. MMWR Morb Mortal Wkly Rep 4021-23,1991 5. Hepatitis E among U.S. travelers, 1989-1992. MMWR Morb Mortal Wkly Rep 42:1-4, 1993 6. Schistosomiasis in US. Peace Corps volunteers-Malawi, 1992 [published erratum appears in MMWR Morb Mortal Wkly Rep 42615, 19931. MMWR Morb Mortal Wkly Rep 42565-570,1993 7. Diphtheria acquired by U.S. citizens in the Russian Federation and Ukraine-1994. MMWR Morb Mortal Wkly Rep 44:237-244, 1995 8. Diphtheria epidemic: New Independent States of the former Soviet Union, 19901994. MMWR Morb Mortal Wkly Rep 45:177-181, 1995 9. Imported d e n g u e u n i t e d States, 1993-1994. MMWR Morb Mortal Wkly Rep 44:353356, 1995 10. Update: management of patients with suspected viral hemorrhagic fever-United States. MMWR Morb Mortal Wkly Rep M475-479, 1995 11. Availability of parenteral quinidine gluconate for treatment of severe or complicated malaria. MMWR Morb Mortal Wkly Rep 45494-495, 1996 12. Imported d e n g u e u n i t e d States, 1995. MMWR Morb Mortal Wkly Rep 45:988991, 1996 13. Update: Diphtheria epidemic: Newly independent states of the former Soviet Union, January 1995March 1996. MMWR Morb Mortal Wkly Rep 45:693-697, 1996 14. Case Definitions for Infectious Conditions under Public Health Surveillance. MMWR Morb Mortal Wkly Rep 464546, 1997 15. Outbreak of leptospirosis among white-water r a f t e r s r o s t a Rica, 1996. MMWR Morb Mortal Wkly Rep 46:577-579,1997 16. Albrecht H, Sobottka I, Emminger C, et al: Visceral leishmaniasis emerging as an important opportunistic infection in HIV-infected persons living in areas nonendemic for Leishmania donovani. Arch Pathol Lab Med 120189-198, 1996 17. Antos H, Mollison LC, Richards MJ, et a 1 Diphtheria: Another risk of travel. J Infect 25~307-310,1992 18. Applebaum GD, Mathisen G: Spinal brucellosis in a southern California resident. West J Med 166:6145,1997 19. Baird J, Basri H, Purnomo, et al: Resistance to chloroquine by Plasmodium vivax in Irian Jaya, Indonesia. Am J Trop Med Hyg 44547-552, 1991 20. Banchongaksorn T, Yomokgul P, Panyim S, et a1 A field trial of the Parasight-F test for the diagnosis of Plasmodium falciparum infection. Trans R SOCTrop Med Hyg 90244-245,1996

464

MAGILL

21. Barat L, Zucker J, Barber A, et a1 Malaria surveillance--United States, 1993. MMWR CDC Surveil1 Summ 469747,1997 22. Barros ML, Boecken G: Jungle yellow fever in the central Amazon [letter]. Lancet 348969-970, 1996 23. Beadle C, Long GW, Weiss WR, et a 1 Diagnosis of malaria by detection of Plasmodium falciparum HRP-2 antigen with a rapid dipstick antigen-capture assay [comments]. Lancet 343:564-568, 1994 24. Blanchard T, Milne L, Pollock R, et al: Early chemotherapy of imported neuroschistosomiasis. Lancet 341:959, 1993 25. Blankfein R, Chirico A Cerebral schistosomiasis. Neurology 15:957-967, 1965 26. Blunt S, Boulton J, Wise R: MRI in schistosomiasis of conus medullaris and lumbar spinal cord. Lancet 341:557, 1993 27. Bradley D Hepatitis E: Epidemiology, aetiology, and molecular biology. Rev Med Virol 2:19-28, 1992 28. Bruni M, Steffen R Impact of travel-related health impairments. J Trav Med 46164,1997 29. Bryan R, Waskin H, Richards F, et al: African trypanosomiasis in American travelers: A 20-year review. Travel Medicine: Proceedings of the first conference on international travel medicine. Zurich, Switzerland, 1988, pp 385-388 30. Chapman PJ, Wilkinson PR, Davidson RN: Acute schistosomiasis (Katayama fever) among British air crew. BMJ 2971101, 1988 31. Clarke V de V, Warburton B, Blair DM: The Katayama syndrome: Report on an outbreak in Rhodesia. Cent Afr J Med 16:123-126,1970 32. Clyde DF, McCarthy VC: Radical cure of Chesson strain yivax malaria in man by 7, not 14, days of treatment with primaquine. Am J Trop Med Hyg 26562-563,1977 33. Collignon P: Chloroquine resistance in Plasmodium vivax. J Infect Dis 164222423, 1991 34. Collignon P: Chloroquine-resistant Plasmodium vivax: It may be a common problem. Med J Australia 157426, 1992 35. Cook G, Bryceson A: Long-standing infection with S. mansoni. Lancet i:127,1988 36. Cunha B A The clinical significance of fever patterns. Infect Dis Clin North Am 10:33-44, 1996 37. Day J, Behrens R Delay in onset of malaria with mefloquine prophylaxis. BMJ 345:398, 1995 38. Day J, Grant A, Doherty J, et al: Schistosomiasis in travelers returning from subSaharan Africa. BMJ 313:268-269, 1996 39. Dietze R, Perkins M, Boulos M, et a1 The diagnosis of Plasmodium falciparum infection using a new antigen detection system [published erratum appears in Am J Trop Med Hyg Jul53:110,1995]. Am J Trop Med Hyg 52:45-49, 1995 40. Doherty JF, Grant AD, Bryceson A D Fever as the presenting complaint of travellers returning from the tropics. QJM 88:277-281, 1995 41. Doherty JF, Moody AH, Wright SG: Katayama fever: An acute manifestation of schistosomiasis. BMJ 313:1071-1072, 1996 42. Dua VK, Kar PK, Sharma VP: Chloroquine resistant Plasmodium vivax malaria in India. Trop Med Int Health 1:816-819, 1996 43. Emmanouilides CE, Kohn OF, Garibaldi R Leptospirosis complicated by a JarischHerxheimer reaction and adult respiratory distress syndrome: Case report [comments]. Clin Infect Dis 181004-1006, 1994 44. Farr RW Leptospirosis. Clin Infect Dis 21:1-6; quiz 7-8, 1995 45. Felton JM, Bryceson AD: Fever in the returning traveller. Br J Hosp Med 55705711, 1996 46. Garavelli P, Corti-E: Chloroquine resistance in Plasmodium vivax: The first case in Brazil. Trans R SOCTrop Med Hyg 86:128, 1992 47. Gasser RA Jr, Magill AJ, Oster CN, et a1 The threat of infectious disease in troops returning from Operation Desert Storm. New Engl J Med 324859-864, 1991 48. Gelfand M Pulmonary schistosomiasis in the early ‘Katayama’ phase of the disease. J Trop Med Hyg 69:143-144, 1966

FEVER IN THE RETUFWED TRAVELER

465

49. Greenberg A, Lobe1 H Mortality from Plasmodium falciparum malaria in travelers from the United States, 1959-1987. Ann Intern Med 113326-327,1990 50. Greenwood B, Armstrong J: Comparison of two simple methods for determining malaria parasite density. Trans R SOCMed Hyg 85:186-188,1991 51. Gubler DJ, Clark G G Dengue/dengue hemorrhagic fever: The emergence of a global health problem. Emerg Infect Dis 1:55-57,1995 52. Gussenhoven GC, van der Hoorn MA, Cons MG, et a1 LEPTO dipstick, a dipstick assay for detection of Leptospira-specific immunoglobulin M antibodies in human sera. J Clin Microbiol35:92-97, 1997 53. Hall AJ: Hepatitis in travellers: Epidemiology and prevention. Br Med Bull 49:382393,1993 54. Hanna J: Chloroquine-resistant Plasmodium vivax: How common? Med J Australia 158:502-503,1993 55. Hassan IS, Ong EL Fever in the returned traveller: Remember murine typhus! [letter]. J Infect 31:173-174, 1995 56. Heppner DJ, Magill A, Gasser RJ, et al: The threat of infectious diseases in Somalia. N Engl J Med 3281061-1068,1993 57. Hill MK, Sanders CV: Leptospiral pneumonia. Semin Respir Infect 1244-49, 1997 58. Hirabayashi Y, Oka S, Goto H, et al: An imported case of Lassa fever with late appearance of polyserositis. J Infect Dis 158872-875, 1988 59. Hoff H, Shaby J: Nervous-and mental manifestations of bilharziasis and their treatment. Trans Roy SOCTrop Med Hyg 33:107-111,1939 60. Humar A, Keystone J: Evaluating fever in travellers returning from tropical countries. BMJ 312955956, 1996 61. Humar A, Ohrt C, Harrington MA, et al: Parasight F test compared with the polymerase chain reaction and microscopy for the diagnosis of Plasmodiumfalciparum malaria in travelers. Am J Trop Med Hyg 5644-48, 1997 62. Humar A, Sharma S, Zoutman D, et a1 Fatal falciparum malaria in Canadian travellers. Can Med Assoc J 156:1165-1167, 1997 63. Isaacson M Airport malaria: A review. Bull WHO 67737-743,1989 64. Istre G, Fontaine R, Tarr J: Acute scistosomiasis among Americans rafting the Om0 River, Ethiopia. Journal of the American Medical Society 251:508-510, 1984 65. Isturiz RE, Stamboulian D, Lepetic A, et al: Health advice for travelers to Latin America [published erratum appears in Infect Dis Clin North Am 8:xii, 1994). Infect Dis Clin North Am 8155-181, 1994 66. Jacobs MG, Brook MG, Weir WR, et a 1 Dengue haemorrhagic fever: A risk of returning home. BMJ 302828-829, 1991 66a. Jelinek T, Dobler G, Holscher M Prevalence of infection with dengue virus among international travelers. Arch Intern Med 1579367-2370, 1997 67. Karbwang J, Tasanor 0,Kanda T, et al: Parasight-F test for the detection of treatment failure in multidrug resistant Plasmodium falciparum malaria. Trans R SOCTrop Med Hyg 90:51?-515, 1996 68. Kawakami A, Fukunaga T, Usui M, et a1 Visceral leishmaniasis misdiagnosed as malignant lymphoma [see comments]. Intern Med 35:502-506,1996 69. Kean B, Reilly P: Malaria-the mime: Recent lessons from a group of civilian travelers. Am J Med 61:159-164, 1976 70. Kenyon RH, Niklasson 8, Jahrling PB, et al: Virologic investigation of a case of suspected haemorrhagic fever. Res Viroll45397406,1994 71. Kumar A, Sharma VP, Thavaselvam D, et al: Clinical trials of a new immunochromatographic test for diagnosis of Plasmodium falciparum malaria in Goa. Indian J Malariol33166-172,1996 72. Kyaw M, 00M, Lwin M, et al: Emergence of chloroquine-resistant Plasmodium vivax in Myanmar (Burma). Trans R Soc Trop Med Hyg 87687, 1993 72a. Laferi H, Kandel K, Pichler H False positive dipstick test for Malaria. New Eng J Med 3371635-1636, 1997 73. Lee KC, Yamazaki 0, Hamba H, et a 1 Analysis of 69 patients with amebic liver abscess. J Gastroenterol31:4@45, 1996 74. Levy L, Baldachin 8, Clain D Intracranial bilharzia. Cent Afr J Med 21:76-84, 1975

466

MAGlLL

75. Lewis S, Davidson R, Ross E, et al: Severity of imported falciparum malaria: Effect of taking antimalarial prophylaxis. BMJ 305741-743,1992 76. Liu LX, Weller P F Approach to the febrile traveler returning from Southeast Asia and Oceania. Curr Clin Top Infect Dis 12:138-164, 1992 77. Lopez-Velez R, Perez-Casas C, Vorndam AV, et al: Dengue in Spanish travelers retuming from the tropics. Eur J Clin Microbiol Infect Dis 15823-826, 1996 78. Lucey D, Maguire J: Schistosomiasis. Infect Dis Clin North Am 7:635-653, 1993 79. Mackowiak P, Bartlett J, Borden E, et a1 Concepts of fever: Recent advances and lingering dogma. Clin Infect Dis 25:119-138,1997 80. MacLean J, Lalonde R, Ward B Fever from the tropics. Travel Medicine Advisor 5:27.1-27.14, 1994 81. Maguire J, Gantz N, Moschella S, et al: Leishmania1 infections: A consideration in travellers returning from abroad. Am J Med Sci 28532-40, 1983 82. Maguire J H Epidemiologic considerations in the evaluation of undifferentiated fever in a traveler retuming from Latin America or the Caribbean. Curr Clin Trop Infect Dis 13:26-56, 1993 83. Makler MT, Hinrichs DJ: Measurement of the lactate dehydrogenase activity of Plasmodium falciparum as an assessment of parasitemia. Am J Trop Med Hyg 48:205210, 1993 84. Marcial-Rojas R, Fiol R Neurologic complications of schistosomiasis: Review of the literature and report of two cases of transverse myelitis due to S . mansoni. Ann Intern Med 59215-230, 1963 85. Marotto PC, Marotto MS, Santos DL, et al: Outcome of leptospirosis in children. Am J Trop Med Hyg 56307-310,1997 86. Marschang A, Nothdurft HD, Kumlien S, et a1 Imported rickettsioses in German travelers. Infection 23:94-97, 1995 87. Martinez-Ocana JC, Serra A, Bonet J, et a1 Acute glomerulonephritis without fever: An unusual presentation of malaria on mefloquine prophylaxis [letter]. Nephron 73:372, 1996 88. Mathieu JJ, Henning KJ, Bell E, et al: Typhoid fever in New York City, 1980 through 1990. Arch Intern Med 1541713-1718,1994 89. McCarthy MA, Carpenter D, Goyette M, et a 1 Dengue fever in Canada. Can Commun Dis Rep 21:185-187,1995 90. McClain J, Ballou W, Harrison S, et al: Doxycycline therapy for leptospirosis. Ann Intern Med 10069Mi98, 1984 90a. Mcfarland JM, Baddour LM, Nelson JE,et a 1 Imported yellow fever in a United States citizen. Clin Infec Dis 25:1143-1147, 1997 91. Miller KD, Greenberg AE, Campbell C C Treatment of severe malaria in the United States with a continuous infusion of quinidine gluconate and exchange transfusion [comments]. N Engl J Med 321:65-70,1989 92. Milne LM, Kyi MS, Chiodini PL, et al: Accuracy of routine laboratory diagnosis of malaria in the United Kingdom. J Clin Pathol47740-742, 1994 93. Misra S, Diaz PS, Rowley A H Characteristics of typhoid fever in children and adolescents in a major metropolitan area in the United States. Clin Infect Dis 24:998-1000, 1997 94. Mockenhaupt F: Mefloquine resistance in Plasmodium falciparum. Parasitology Today 11:24&253, 1995 95. Monsuez JJ,Kidouche R, Le Gueno 8, et a 1 Leptospirosis presenting as haemorrhagic fever in visitor to Africa [letter]. Lancet 3493254-255, 1997 96. Murphy G, Basri H, Pumomo, et a 1 Vivax malaria resistant to treatment and prophylaxis with chloroquine. Lancet 341:96-100, 1993 97. Na-Bangchang K,Molunto P, Banmairuroi V, et al: Pharmacokinetics of mefloquine when given as a single and two divided-dose regimens. Int J Clin Pharmacol Res 15:215-220, 1995 98. Neuvonen P, Penttila 0, Lehtovaara R, Ah0 K Effect of antiepileptic drugs on the elimination of various tetracycline derivatives. Eur J Clin Pharrnacol9:147-154,1975 99. O’Neil KM, Rickman LS, Lazarus AA: Pulmonary manifestations of leptospirosis. Rev Infect Dis 13705-709, 1991

FEVER IN THE RETURNED TRAVELER

467

100. Oster CN, Tramont EC: Fever in a recent visitor to the Middle East. Curr Clin Top Infect Dis 1357-73, 1993 101. Panosian CB, Cohen L, Bruckner D, et al: Fever, leukopenia, and a cutaneous lesion in a man who had recently traveled in Africa [clinical conference]. Rev Infect Dis 13:1131-1138, 1991 102. Parkas V, Godwin J, Murray Hw.Kala-azar comes to New York. Arch Intern Med 157921-923,1997 103. Phillips EJ, Keystone JS, Kain K C Failure of combined chloroquine and high-dose primaquine therapy for Plasmodium vivax malaria acquired in Guyana, South America [comments]. Clin Infect Dis 23:1171-1173, 1996 104. Pitkanen YT, Peltonen M, Lahdevirta J, et a1 Acute schistosomiasis mansoni in Finnish hunters visiting Africa: Need for appropriate diagnostic serology. S a n d J Infect Dis 22597400,1990 105. Pollner J, Schwartz A, Kobrine A, et a 1 Cerebral schistosomiasis caused by Schisfosoma haemafobium [case report]. Clin Infect Dis 18354-357,1994 106. Premji Z, Minjas JN, Shiff CJ: Laboratory diagnosis of malaria by village health workers using the rapid manual Parasight-F test. Trans R SOCTrop Med Hyg 88:418, 1994 107. Puente S, Lago M, Subirats M, et a1 Spotted fever attributable to Rickettsia conorii: Ten cases imported from Sub-Saharan Africa. J Trav Med 2204-205, 1995 108. Raeber PA, Winteler S, Paget J: Fever in the returned traveller: Remember rickettsia1 diseases [letter]. Lancet M 3 3 1 , 1994 109. Raglio A, Parea M, Francesca V, et a1 A family case report of Schistosoma haematobium infection in Italian travelers. J Trav Med 2193-195, 1995 110. Rieckman K, Davis D, Hutton D: Plasmodium vivax resistance to chloroquine? Lancet ik1183-1184, 1989 111. Rigau-Perez JG, Gubler DJ, Vorndam AV, et a1 Dengue surveillance-United States, 1986-1992. MMWR CDC Surveil1 Summ 437-19, 1994 112. Robertson SE, Hull BP, Tomori 0, et a1 Yellow fever: A decade of reemergence. JAMA 276:1157-1162, 1996 113. Robson J, Conroy D, Cremin J, et a1 Chloroquine-resistant Plasmodium vivax: How common? Med J Australia 158:502,1993 114. Rosenthal PJ, Petersen C, Geertsma FR, et al: Availability of intravenous quinidine for falciparum malaria [letter]. N Engl J Med 335:138, 1996 115. Rowe B, Threlfall E, Ward L: Ciprofloxacin and typhoid fever. Lancet 339:740, 1992 116. Rowe B, Threlfall E, Ward L Ciprofloxacin-resistant Salmonella typhi in the United Kingdom. Lancet 346:1302,1995 117. Rowe 8, Ward LR, Threlfall EJ: Multidrug-resistant Salmonella typhi: A worldwide epidemic. Clin Infect Dis 24(Suppl 1):106-109, 1997 118. Saeed A, Magzoub M: An outbreak of Schistosoma mansoni infection in a European c o m r n ~ t yin Darfur, Western Sudan. Ann Trop Med Parasitol 6 8 4 0 5 4 3 , 1974 119. Schmitz H, Emmerich P, ter Meulen J: Imported tropical virus infections in Germany. Arch Virol ll(Suppl):67-74, 1996 120. Schuurkamp G, Spicer P, Kereu R, et a1 A mixed infection of vivax and falciparum malaria apparently resistant to 4-aminoquinoline: A case report. Trans R SOCTrop Med Hyg 83607408,1989 121. Schuurkamp G, Spicer P, Kereu R, et a 1 Chloroquine-resistant Plasmodium vivax in New Guinea. Trans R Soc Trop Med Hyg 86121-122,1992 122. Schwartz E, Mendelson E, Sidi Y: Dengue fever among travelers. Am J Med 101:516520, 1996 123. Schwartz E, Shlim DR, Eaton M, et a 1 The effect of oral and parenteral typhoid vaccination on the rate of infection with Salmonella typhi and Salmonella paratyphi A among foreigners in Nepal [comments]. Arch Intern Med 15039-351,1990 124. Schwartz I, Lackritz E, Patchen L: Chloroquine-resistant Plasmodium vivax from Indonesia. N Engl J Med 324927,1991 125. Schwarz TF, Jager G, Gilch S, et al: Travel-related vector-borne virus infections in Germany. Arch Virol ll(suppl):5745, 1996

468

MAGILL

126. Scrimgeour E, Gajdusek D Involvement of the central nervous system in Schistosoma mansoni and S. haematobium infection: A review. Brain 108:1023-1038, 1985 127. Scully R, Mark E, McNealy B A 21-year-old man with fever, diarrhea, and weakness of the legs during a sojourn in Kenya. N Engl J Med 312137&1383,1985 128. Shekhar K Schistosomiasis drug therapy and treatment considerations. Drugs 42:379, 1991 129. Singh N, Singh MP, Sharma VP: The use of a dipstick antigen-capture assay for the diagnosis of Plasmodium fakiparum infection in a remote forested area of central India. Am J Trop Med Hyg 56:188-191, 1997 130. Skaug K, Hagen IJ, von der Lippe B Three cases of acute hepatitis E virus infection imported into Norway. Scand J Infect Dis 26137-139, 1994 131. Smoak BL, McClain JB, Brundage JF,et a1 An outbreak of spotted fever rickettsiosis in U.S. Army troops deployed to Botswana. Emerg Infect Dis 2:217-221, 1996 132. Steffen R Hepatitis A and hepatitis B: Risks compared with other vaccine preventable diseases and immunization recommendations. Vaccine 11:518-520, 1993 133. Strickland GT Fever in the returned traveler. Med Clin North Am 76:1375-1392,1992 134. Stuiver P, Rijswijk JV,Visser L: Delayed onset of malignant tertian malaria through the inappropriate use of doxycycline: Another threat to patients returning from malarious areas. J Trav Med 3193, 1996 135. Stuiver PC: Acute schistosomiasis (Katayama fever). BMJ 288:221-222, 1984 136. Svenson JE, Gyorkos TW, MacLean JD: Diagnosis of malaria in the febrile traveler. Am J Trop Med Hyg 53:518-521,1995 137. Svenson JE, MacLean JD, Gyorkos TW, et a1 Imported malaria: Clinical presentation and examination of symptomatic travelers. Arch Intern Med 1552361-868, 1995 138. Takafuji E, Kirkpatrick J, Miller R An efficacy trial of doxycycline chemoprophylaxis against leptospirosis. N Engl J Med 310:497-500, 1984 139. Thiebaut MM, Bricaire F, Raoult D Scrub typhus after a trip to Vietnam [letter]. N Engl J Med 336:1613-1614, 1997 140. Tsang V, Wilkins P: Immunodiagnosis of schistosomiais: Screen with FAST-ELISA and confirm with immunoblot. Clin Lab Med 11:1029-1039,1991 141. Uguen C, Rabodonirina M, De Pina JJ, et al: Parasight-F rapid manual diagnostic test of Plasmodium fakiparum infection. Bull WHO 736434549, 1995 142. Umasankar S, Wall R, Berger J: A case of ciprofloxacin-resistant typhoid fever. CDR Review 2139-140, 1992 143. van Crevel R, Speelman P, Gravekamp C, et al: Leptospirosis in travelers. Clin Infect Dis 19~132-134,1994 144. Vaughan C, Cronin CC, Walsh EK, et al: The Jarisch-Herxheimer reaction in leptospirosis. Postgrad Med J 70118-121, 1994 145. Verle P, Binh LN, Lieu TT, et al: Parasight-F test to diagnose malaria in hypo-endemic and epidemic prone regions of Vietnam. Trop Med Int Health 1:794-796, 1996 146. Visser LG, Polderman AM, Stuiver P C Outbreak of schistosomiasis among travelers returning from Mali, West Africa. Clin Infect Dis 20:280-285, 1995 147. Wade B Deadly vacations: Vaccinations are necessary as life itself: Chicago Tribune. Chicago, 1996, p 14 148. Watt G, Padre LP, Tuazon ML, et a1 Placebo-controlled trial of intravenous penicillin for severe and late leptospirosis. Lancet 1:433-435, 1988 149. Watt G, Strickman D: Life-threatening scrub typhus in a traveler returning from Thailand. Clin Infect Dis 183624426, 1994 150. Wetsteyn J, Geus A D Chloroquine-resistant falciparum malaria imported into the Netherlands. Bull WHO 63:lOl-108, 1985 151. Whitby M, Wood G, Veenendaal J, et al: Chloroquine-resistant PZasmodium uivax. Lancet ii:1395, 1989 152. Wilks D, Jacobson SK, Lever AM, et al: Fatal melioidosis in a tourist returning from Thailand. J Infect 29:87-90, 1994 153. Wilson M: A World Guide to Infections: Diseases, Distribution, Diagnosis. New York, Oxford University Press, 1991 154. Winters RA, Murray Kw. Malaria-the mime revisited: Fifteen more years of experience at a New York City teaching hospital [comments]. Am J Med 93:243-246, 1992

FEVER IN THE RETURNED TRAVELER

469

155. Wittesjo B, Eitrem R, Niklasson B Dengue fever among Swedish tourists. Scand J Infect Dis 25:699-704, 1993 156. Woodward T: The fever pattern as a diagnostic aid: In Mackowiak P (ed): Fever: Basic Mechanisms and Management. New York, Raven Press, 1991, pp 71-82 156a. World Health Organization. Division of Control of Tropical Disease: Severe and Complicated Malaria. Trans R Soc Trop Med Hyg. 84(supp 2):1-65, 1996 157. Wyler DJ: Evaluation of cryptic fever in a traveler to Africa. CUR Clin Top Infect Dis 12329447,1992 158. Xiao S, Catto B, Webster L: Effects of praziquantel on different developmental stages of Schistosom mnsoni in vitro and in vivo. J Infect Dis 151:1130, 1985 159. Zaki SR, Shieh WJ: Leptospirosis associated with outbreak of acute febrile illness and pulmonary haemorrhage, Nicaragua, 1995. The Epidemic Working Group at Ministry of Health in Nicaragua [letter] [comments]. Lancet 347535-536, 1996 160. Zucker J: Changing patterns of autochthonous malaria transmission in the United States: A review of recent outbreaks. Emerg Infect Dis 237-43, 1996 161. Zucker JR, Barber AM, Paxton LA, et al: Malaria surveillance-United States, 1992. MMWR CDC Surveill S u m 443-17,1995 162. Zuidema PJ: The Katayama syndrome: An outbreak in Dutch tourists to the Om0 National Park, Ethiopia. Trop Geogr Med 33:30-35, 1981

Address reprint requests to Alan J. Ma@, MD US NAMRID, Unit 3800 APO AA, 34031-3800